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European Journal of Heart Failure Apr 2023Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are...
AIMS
Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR-CM.
METHODS AND RESULTS
Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. The study population consisted of 2029 patients with ATTR-CM (median age 79 years at diagnosis, 13.5% females, 80.4% Caucasian). Variant ATTR-CM (ATTRv-CM) was diagnosed in 20.7% (n = 421) of the study population of whom 327 (77.7%) carried V122I, 47 (11.2%) T60A, 16 (3.8%) V30M and 31 (7.3%) other pathogenic TTR variants. During a median (range) follow-up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p < 0.001). Univariable and multivariable logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p < 0.001), female sex (OR 2.73, p < 0.001), Afro-Caribbean ethnicity (OR 65.5, p < 0.001), atrial fibrillation (OR 0.65, p = 0.015), ischaemic heart disease (OR 0.54, p = 0.007), peripheral polyneuropathy (OR 5.70, p < 0.001) and orthostatic hypotension (OR 6.29, p < 0.001) to be independently associated with ATTRv-CM.
CONCLUSION
Up to 20.7% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age.
Topics: Aged; Humans; Female; Aged, 80 and over; Male; Prevalence; Prealbumin; Amyloid Neuropathies, Familial; Retrospective Studies; Heart Failure; Cardiomyopathies
PubMed: 36644836
DOI: 10.1002/ejhf.2776 -
Genes Jun 2021The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble... (Review)
Review
The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.
Topics: Amyloid Neuropathies, Familial; Amyloidosis, Familial; Extracellular Matrix Proteins; Eye Diseases; Gelsolin; Genetic Predisposition to Disease; Humans; Prealbumin; Retinal Pigment Epithelium; Transforming Growth Factor beta
PubMed: 34206500
DOI: 10.3390/genes12070955 -
Annals of Clinical and Translational... Sep 2022To determine the sensitivity and specificity of cutaneous amyloid deposition in relation to patient-reported measures in the earliest disease stage of hereditary ATTR...
OBJECTIVE
To determine the sensitivity and specificity of cutaneous amyloid deposition in relation to patient-reported measures in the earliest disease stage of hereditary ATTR amyloidosis (ATTRv).
METHODS
In a cross-sectional study, we analyzed 88 individuals with TTR mutations, 47 of whom were in the earliest disease stage and without clinically evident neuropathy, 12 healthy controls, and 13 disease controls with diabetes. All participants' neuropathy symptoms and signs were assessed using validated patient and clinician-reported measures and 3-mm skin punch biopsies were immunostained using protein gene product 9.5 and Congo Red.
RESULTS
Amyloid can be detected in the earliest disease stages in up to 86% of patients with ATTRv amyloidosis. Amyloid was not detected in healthy individuals or individuals with diabetic peripheral neuropathy supporting a sensitivity of 86% and a specificity of 100%. The cutaneous deposition of amyloid correlates with neuropathy sensory symptoms, measured with the Neuropathy Total Symptom Score-6 (R = 0.46, p < 0.01); pain measured with the Brief Pain Symptom Inventory (R = 0.44, p < 0.05); autonomic symptoms, measured with the Boston Autonomic Symptom Questionnaire (R = 0.38, p < 0.05); and quality of life measured with the Norfolk Diabetic Neuropathy Quality of Life Questionnaire (R = 0.44, p < 0.05). Individuals with amyloid deposition were more likely to have sensory symptoms, pain, autonomic impairment, and reduced quality of life than ATTRv patients without amyloid deposition.
INTERPRETATION
These findings have implications for understanding the earliest manifestations of the clinical phenotype of ATTRv-associated neuropathy, for the pathophysiological construct of disease staging, and for timing the introduction of disease-modifying therapy.
Topics: Amyloid; Amyloid Neuropathies, Familial; Biomarkers; Cross-Sectional Studies; Diabetic Neuropathies; Humans; Pain; Quality of Life
PubMed: 35945901
DOI: 10.1002/acn3.51636 -
Journal of Clinical Pharmacology Jan 2020Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin... (Randomized Controlled Trial)
Randomized Controlled Trial
Patisiran Pharmacokinetics, Pharmacodynamics, and Exposure-Response Analyses in the Phase 3 APOLLO Trial in Patients With Hereditary Transthyretin-Mediated (hATTR) Amyloidosis.
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by deposition of abnormal transthyretin protein. Patisiran is an RNA interference therapeutic comprising a novel, small interfering ribonucleic acid (ALN-18328) formulated in a lipid nanoparticle targeted to inhibit hepatic transthyretin protein synthesis. The lipid nanoparticle also contains 2 novel lipid excipients (DLin-MC3-DMA and PEG -C-DMG). Here we report patisiran pharmacokinetics (PK), pharmacodynamics (PD), and exposure-response analyses from the phase 3 APOLLO trial, in which patients with hATTR amyloidosis with polyneuropathy were randomized 2:1 to receive patisiran 0.3 mg/kg or placebo intravenously every 3 weeks over 18 months. In patisiran-treated patients, mean maximum reduction in serum transthyretin level from baseline was 87.8%. Patisiran PK exposure was stable following chronic dosing. There were no meaningful differences in PK exposure, serum transthyretin reduction, and efficacy (change from baseline in modified Neuropathy Impairment Score+7) across all subgroups analyzed (age, sex, race, body weight, genotype status of valine-to-methionine mutation at position 30 [V30M] and non-V30M, prior use of tetramer stabilizers, mild/moderate renal impairment, and mild hepatic impairment). transthyretin reduction and efficacy were similar across the interpatient PK exposure range for ALN-18328. There was no trend in the incidence of adverse events or serious adverse events across the interpatient PK exposure range for all 3 analytes. Incidence of antidrug antibodies was low (3.4%) and transient, with no impact on PK, PD, efficacy, or safety. The patisiran dosing regimen of 0.3 mg/kg every 3 weeks is appropriate for all patients with hATTR amyloidosis.
Topics: Administration, Intravenous; Aged; Amyloid Neuropathies, Familial; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Liposomes; Liver; Male; Middle Aged; Nanoparticles; Polyneuropathies; Prealbumin; RNA, Small Interfering; RNAi Therapeutics; Treatment Outcome
PubMed: 31322739
DOI: 10.1002/jcph.1480 -
Methodist DeBakey Cardiovascular Journal 2022Just a few years ago, cardiac amyloidosis (CA) was rarely diagnosed. With poor treatment options and delayed and infrequent diagnoses, most patients who were eventually... (Review)
Review
Just a few years ago, cardiac amyloidosis (CA) was rarely diagnosed. With poor treatment options and delayed and infrequent diagnoses, most patients who were eventually recognized to have CA were referred for hospice care. Now, the availability of sponsored genetic testing, increased use of nuclear scintigraphy, and widespread recognition have contributed to an increasing number of patients being diagnosed with transthyretin amyloid cardiomyopathy (ATTR-CM). Concomitantly, with the increased recognition of concurrent conditions (eg, carpal tunnel syndrome, lumbar stenosis, and low-flow, low-gradient aortic stenosis), specialists such as orthopedic surgeons and structural cardiologists are increasingly involved in diagnosing ATTR-CM. Although the majority of patients are still being diagnosed either too late or having their diagnosis missed altogether, we have entered an exciting new era in the treatment of cardiac amyloidosis with improved diagnostic tools, disease recognition, and different therapeutic options for both ATTR and light-chain amyloidosis (AL). As a result, survival is improving, and we are no longer faced with a dualistic choice between hospice or organ transplant. The future goal is to develop anti-fibril therapies that will be safe and effective at removing deposited amyloid fibrils and restoring organs to their pre-amyloid state. For the millions of carriers of variant ATTR, enhanced testing followed by genetic editing may allow a cure even before patients develop clinical signs of the disease.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Humans
PubMed: 35414857
DOI: 10.14797/mdcvj.1071 -
European Journal of Heart Failure Feb 2021
Topics: Amyloid Neuropathies, Familial; Heart Failure; Humans; Prealbumin
PubMed: 33342016
DOI: 10.1002/ejhf.2080 -
CMAJ : Canadian Medical Association... Apr 2024
Topics: Humans; Carpal Tunnel Syndrome; Amyloid Neuropathies, Familial
PubMed: 38621774
DOI: 10.1503/cmaj.230671-f -
BMJ Case Reports Aug 2019
Topics: Aged, 80 and over; Amyloid Neuropathies, Familial; Bone and Bones; Cardiomyopathies; Echocardiography; Heart Failure; Humans; Hypertrophy, Left Ventricular; Male; Radionuclide Imaging; Transcatheter Aortic Valve Replacement; Treatment Outcome
PubMed: 31473644
DOI: 10.1136/bcr-2019-231793 -
Heart Failure Reviews Mar 2024Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by the deposition of abnormal transthyretin protein fibrils in the heart, leading to... (Review)
Review
Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by the deposition of abnormal transthyretin protein fibrils in the heart, leading to cardiac dysfunction. Recent evidence suggests that sex differences may play a significant role in various steps of ATTR-CA, including clinical presentation, diagnostic challenges, disease progression, and treatment outcomes. ATTR-CA predominantly affects men, whereas women are older at presentation. Women generally present with a history of heart failure with preserved ejection fraction and/or carpal tunnel syndrome. When indexed, left ventricular (LV) wall thickness is equal, or even increased, than men. Women also have smaller LV cavities, more preserved ejection fractions, and apparently a slightly worse right ventricular and diastolic function. Given the under-representation on women in clinical trials, no data regarding sex influence on the treatment response are currently available. Finally, it seems there are no differences in overall prognosis, even if premenopausal women may have a certain level of myocardial protection. Genetic variations, environmental factors, and hormonal changes are considered as potential contributors to observed disparities. Understanding sex differences in ATTR-CA is vital for accurate diagnosis and management. By considering these differences, clinicians can improve diagnostic accuracy, tailor treatments, and optimize outcomes for both sexes with ATTR-CA.
Topics: Humans; Female; Male; Cardiomyopathies; Prealbumin; Sex Characteristics; Amyloidosis; Heart; Amyloid Neuropathies, Familial
PubMed: 37566193
DOI: 10.1007/s10741-023-10339-w -
Arquivos Brasileiros de Oftalmologia 2022Transthyretin familial amyloidosis is the most common form of inherited systemic amyloidosis worldwide. The condition develops secondary to more than 100 different point... (Review)
Review
Transthyretin familial amyloidosis is the most common form of inherited systemic amyloidosis worldwide. The condition develops secondary to more than 100 different point mutations in the transthyretin gene (18q12.1). The mutations lead to abnormal amyloid deposits, mainly in the heart and peripheral nerves. Leptomeningeal and mainly ocular involvement is common. Although there are several different types of treatment available, ocular involvement, which occurs also in liver transplant recipients, remains a major challenge, progressing even in liver transplant recipients. Patients with ocular involvement require efficient ophthalmological follow-up to prevent vision loss. In this review, different forms of ocular involvement characterizing the subtypes of transthyretin mutations were described, and the effects of different treatments were summarized. Further research is necessary to fully elucidate these issues.
Topics: Amyloid Neuropathies, Familial; Humans; Mutation; Prealbumin
PubMed: 35417510
DOI: 10.5935/0004-2749.20220099